US7268157B2 - Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity - Google Patents

Substituted arylalcanoic acid derivatives as PPAR pan agonists with potent antihyperglycemic and antihyperlipidemic activity Download PDF

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US7268157B2
US7268157B2 US10/715,622 US71562203A US7268157B2 US 7268157 B2 US7268157 B2 US 7268157B2 US 71562203 A US71562203 A US 71562203A US 7268157 B2 US7268157 B2 US 7268157B2
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alkyl
aryl
amino
alk
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US20040142921A1 (en
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Xian-Ping Lu
Zhibin Li
Chenzhong Liao
Leming Shi
Zhende Liu
Baoshun Ma
Zhiqiang Ning
Song Shan
Tuo Deng
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Chipscreen Biosciences Ltd
Research Institute of Tsinghua University
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Chipscreen Biosciences Ltd
Research Institute of Tsinghua University
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Priority to ES03772525T priority patent/ES2382312T3/es
Priority to AT03772525T priority patent/ATE540925T1/de
Priority to KR1020057008310A priority patent/KR20050075386A/ko
Priority to EP03772525A priority patent/EP1569904B1/en
Priority to AU2003280154A priority patent/AU2003280154B2/en
Priority to PT03772525T priority patent/PT1569904E/pt
Priority to SI200332127T priority patent/SI1569904T1/sl
Priority to PCT/IB2003/005371 priority patent/WO2004048333A1/en
Priority to JP2005510266A priority patent/JP4750556B2/ja
Priority to CA2504718A priority patent/CA2504718C/en
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Priority to HK06102981.1A priority patent/HK1083021A1/xx
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Definitions

  • the present invention relates to the preparation and pharmaceutical use of novel substituted arylalcanoic acid derivatives. More particularly, the present invention relates to novel compounds of the general Formula (I), their preparation methods, their pharmaceutical compositions and their use for treatment and/or prevention of conditions mediated by nuclear receptors, in particular the RXR and PPAR heterodimers.
  • the present compounds are useful in treatment and/or prevention of type 2 diabetes and associated metabolic syndrome such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders with improved side effects profile commonly associated with conventional PPARgamma agonists.
  • Metabolic syndrome including type 2 diabetes and associated complications such as obesity, cardiovascular symptoms, and dyslipidemia, are of major impact on social and economic significance. Although anti-diabetic treatments improve insulin resistance, they offer little protection from eminent cardiovascular risk associated with type 2 diabetes. Therefore, development of new treatments that have insulin sensitizing and cholesterol/triglycerides-lowering effects are of general interest.
  • Diabetes mellitus is a polygenic disorder affecting a significant portion of the people in the world. It is divided into two types. In type 1 diabetes, or insulin-dependent diabetes mellitus (IDDM), patients produce little or no insulin, the hormone that regulates glucose utilization. In type 2 diabetes, or noninsulin dependent diabetes mellitus (NIDDM), patients often have plasma insulin levels that are at the same compared to nondiabetic humans; however, these patients have developed a resistance to the insulin stimulating effect on glucose and lipid metabolism in the main insulin-sensitive tissues, i.e., muscle, liver and adipose tissues, and the plasma insulin levels are insufficient to overcome the pronounced insulin resistance. Type 2 diabetes consists of over 90% of all diabetes. It is a metabolic disorder characterized by hyperglycemia leading to secondary complications such as neuropathy, nephropathy, retinopathy, hypertriglyceridemia, obesity, and other cardiovascular diseases generally referred as metabolic syndrome.
  • the treatment generally prescribed for type 2 diabetes has been a combination of diet, exercise, and oral hypoglycemic agents, commonly sulfonylurea and biguanides.
  • sulfonylurea therapy has many problems associated with primary and secondary failure of efficacy, incidence of hypoglycemia, and obesity.
  • the biguanides therapy can induce lactic acidosis, nausea and diarrhea.
  • a drug that can control plasma glucose tightly without significant side effects would be an important addition to diabetes therapy.
  • thiazolidinediones has been shown to reduce hyperglycemia by promoting insulin action without additional insulin secretion, and without causing undesirable hypoglycemia, even at elevated doses.
  • PPARgamma-selective ligands induce adipocyte differentiation and white fat accumulation that leads to obesity, an important factor linking directly to the onset or the consequence of type 2 diabetes. Such unwanted effects will eventually compromise the insulin-sensitizing benefit of PPARgamma ligands.
  • PPARgamma is a member of ligand-activated nuclear hormone receptor superfamily and expressed primarily in adipose tissues.
  • a class of ligands named fibrates that are known to have triglyceride- and cholesterol-lowering activity activates another member of this family, the PPARalpha, which is mainly expressed in tissues such as liver.
  • PPARalpha stimulates peroxisomal proliferation that enhances fatty acid oxidation, leading to reduced fatty acids level in blood (Keller and Wahli: Trends Endocrin Metab 1993, 4:291-296).
  • PPARdelta was reported to modulate lipid metabolism in which PPARdelta serves as a widespread regulator of fat burning.
  • PPARdelta-deficient mice challenged with high-fat diet show reduced energy uncoupling and are prone to obesity (Wang Y X et al., Cell 2003 Apr. 18; 113(2):159-70).
  • the transcriptional repression of atherogenic inflammation by ligand-activated PPARdelta was also reported, which further indicates the importance of PPARdelta in combating cardiovascular diseases (Lee, C H et al., Science 302:453-457, 2003).
  • PPARalpha, gamma, and delta form heterodimers with Retinoid X Receptor The RXR/PPAR heterodimers thus play an essential role in controlling and regulating cellular events such as lipid, glucose homeostasis, and adipocyte differentiation.
  • RXR/PPAR heterodimers thus play an essential role in controlling and regulating cellular events such as lipid, glucose homeostasis, and adipocyte differentiation.
  • Several new chemical compounds were reported to have either PPARgamma activity or PPAR alpha and gamma dual activities that are beneficial in the treatment and/or prevention of metabolic syndromes in animal and in men (WO 00/08002, WO 01/57001 A1, U.S. Pat. No. 6,054,453, EP 088317 B1, WO97/25042, WO02/26729 A2, and U.S. Pat. No. 6,353,018 B1).
  • novel pan agonists that activate PPAR alpha, gamma, and delta should therefore be a very important addition to bring comprehensive management for metabolic syndrome X such as diabetes, hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders.
  • One aspect of the present invention provides compounds of the Formula I:
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O, S, or NR 6 wherein R 6 represents H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 1 is H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino;
  • R 2 is H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 3 is H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, heterocyclyl, aryl, or heteroaryl;
  • R 4 and R 5 are independently H, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl, hydroxyalkyl, thioalkyl, heterocyclyl, OH, halogen, alkoxy, aryl, aryloxy, aralkoxy, heteroaryl, heteroaryloxy, heteroaralkoxy, acyl, acyloxy, amino, alkylamino, arylamino, or aralkylamino; R 4 and R 5 may form a 5 or 6 membered ring optionally substituted with one or more halogen, hydroxy, nitro, cyano, alkyl, alkenyl, alkenynyl, aralkyl, heteroarylalkyl, aminoalkyl, alkoxyalkyl, aryloxyalkyl, aralkoxyalkyl
  • Alk 1 represents C 1-6 alkylene
  • Alk 2 represents C 1-2 alkylene
  • Ar 1 represents arylene, hetero arylene, or a divalent heterocyclic group optionally substituted with one or more halogen, C 1-6 alkyl, amino, hydroxy, C 1-6 alkoxyl or aryl.
  • Ar 2 represents an aryl group substituted with none, one or more halogen, C 1-6 -alkyl, amino, hydroxy, C 1-6 alkoxyl or aryl; a hetero aryl, or a heterocyclic group optionally substituted with one or more halogen, C 1-6 alkyl, amino, hydroxy, C 1-6 alkoxyl or aryl.
  • Another aspect of the present invention relates to a pharmaceutical composition containing an active ingredient, at least one of the compounds of the general Formula (I), and/or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent for treatment and/or prevention of type 2 diabetes and associated metabolic syndrome such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders.
  • a pharmaceutically acceptable carrier or diluent such as hypertension, obesity, insulin resistance, hyperlipidemia, hyperglycemia, hypercholesterolemia, atherosclerosis, coronary artery disease, and other cardiovascular disorders.
  • the compounds of Formula I are able to decrease hyperglycemia and hypertriglyceremia associated with type 2 diabetes. It was also unexpectedly discovered that the compounds of Formula I can be used as pan agonists for RXR/PPARalpha, RXR/PPARgamma, and RXR/PPARdelta heterodimers, as well as agents for lowering both glucose and triglycerides levels for treatment and/or prevention of type 2 diabetes and associated metabolic syndrome.
  • FIG. 1 graphically illustrates comparative activation of RXR/PPAR alpha heterodimers by compounds of the present invention (Example 30).
  • FIG. 2 shows comparative activation of RXR/PPAR gamma heterodimers by compounds of the present invention (Example 31).
  • FIG. 3 graphically illustrates comparative activation of RXR/PPAR delta heterodimers by compounds of the present invention (Example 32).
  • FIG. 4 shows comparative activation of RXR/PPAR alpha heterodimers by compounds of the present invention (Example 33).
  • FIG. 5 shows comparative activation of RXR/PPAR gamma heterodimers by compounds of the present invention (Example 33).
  • FIG. 6 shows comparative activation of RXR/PPAR delta heterodimers by compounds of the present invention (Example 33).
  • FIG. 7 graphically illustrates in vivo blood glucose lowering affected by a compound of the present invention (Example 34).
  • FIG. 8 graphically illustrates increased insulin sensitivity affected in vivo by a compound of the present invention (Example 35).
  • FIG. 9 graphically illustrates increased glucose tolerance affected in vivo by a compound of the present invention (Example 36).
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a 6 membered aromatic ring
  • ring B is a 6 membered aromatic ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H or alkyl
  • R 2 is H or alkyl
  • R 3 is H or alkyl
  • R 4 and R 5 are independently H or alkyl
  • Alk 1 is C 2-3 alkylene
  • Alk 2 is C 1-2 alkylene
  • Ar 1 is an arylene group
  • Ar 2 is a substituted aryl group.
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a 6 membered aromatic ring
  • ring B is a 6 membered aromatic ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H or alkyl
  • R 2 is H or alkyl
  • R 3 is H or alkyl
  • R 4 and R 5 form a 6 membered aromatic ring
  • Alk 1 is C 2-3 alkylene
  • Alk 2 is C 1-2 alkylene
  • Ar 1 is 6 membered aromatic ring
  • Ar 2 is a substituted aryl group.
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a benzene ring
  • ring B is a benzene ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H
  • R 2 is H
  • R 3 is H
  • R 4 is methyl; R 5 is H;
  • Alk 1 is CH 2 CH 2 ;
  • Alk 2 is CH 2 ;
  • Ar 1 is benzene ring
  • Ar 2 is benzene ring substituted with none, one or more fluorine.
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a benzene ring
  • ring B is a benzene ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H
  • R 2 is H
  • R 3 is H
  • R 4 and R 5 form a benzene ring
  • Alk 1 is CH 2 CH 2 ;
  • Alk 2 is CH 2 ;
  • Ar 1 is benzene ring
  • Ar 2 is benzene ring substituted with none, one or more fluorine.
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a benzene ring
  • ring B is a benzene ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H
  • R 2 is H
  • R 3 is H
  • R 4 is methyl; R 5 is H;
  • Alk 1 is CH 2 CH 2 ;
  • Alk 2 is CH 2 ;
  • Ar 1 is benzene ring
  • Ar 2 is pyridine ring substituted with none, one or more halogen.
  • the compounds of this invention are those of the Formula I, wherein
  • ring A is a benzene ring
  • ring B is a benzene ring
  • X is a valence bond, CH 2 CH 2 , CH ⁇ CH, O or S;
  • R 1 is H
  • R 2 is H
  • R 3 is H
  • R 4 and R 5 form a benzene ring
  • Alk 1 is CH 2 CH 2 ;
  • Alk 2 is CH 2 ;
  • Ar 1 is benzene ring
  • Ar 2 is pyridine ring substituted with none, one or more fluorine.
  • alkyl as used herein is intended to include those alkyl groups in either a linear or branched or cyclic configuration. Typical alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, tert-butyl, penyl, iso-pentyl, hexyl, iso-hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and the like.
  • aralkyl refers to a straight or branched saturated carbon chain containing from 1 to 6 carbons substituted with an aromatic carbohydride, such as benzyl, phenethyl, 3-phenylpropyl, 1-naphtylmethyl and the like.
  • heteroaryl refers to a strait or branched saturated carbon chain containing from 1 to 6 carbons substituted with a heteroaryl as defined herein, such as (2-furyl)methyl, (3-furyl)methyl, (2-pyridyl)methyl and the like.
  • aminoalkyl refers to an alkyl as defined herein whereto is attached an amino group, such as aminoethyl, 1-aminopropyl, 2-aminopropyl and the like.
  • alkoxyalkyl refers to an alkyl as defined herein whereto is attached an alkoxy as defined herein, such as methoxymethyl, ethoxymethyl, methoxyethyl, ethoxyethyl and the like.
  • aryloxyalkyl refers to an alkyl as defined herein whereto is attached an aryloxy as defined herein, such as phenoxymethyl, phenoxydodecyl, 1-naphthyloxyethyl and the like.
  • aralkoxyalkyl refers to an alkyl as defined herein whereto is attached an aralkoxy as defined herein, such as benzyloxymethyl, 3-phenylpropoxyethyl and the like.
  • hydroxyalkyl refers to an alkyl as defined herein whereto is attached a hydroxy group, such as hydroxyethyl, 1-hydroxypropyl, 2-hydroxypropyl and the like.
  • thioalkyl refers to an alkyl as defined herein whereto is attached a group of Formula of —SR′ wherein R 1 is H, alkyl or aryl, such as thiomethyl, methylthiomethyl, phenylthioethyl and the like.
  • heterocyclyl as used herein means a monovalent saturated or unsaturated group being monocyclic and containing one or more heteroatoms, such as pyrrolidine, pyrroline, pyrazoline, imidazolidine, imidazoline, piperidine, morpholine and the like.
  • halogen as used herein means fluorine, chlorine, bromine or iodine.
  • alkoxy as used herein is intended to include those alkyl groups in either a linear or branched or cyclic configuration linked through an ether oxygen having its free valence bond from the ether oxygen, such as methoxy, ethoxy, propoxy, butoxy, pentoxy, isopropoxy, sec-butoxy, cyclopropyloxy, cyclohexyloxy and the like.
  • aryl as used herein is intended to include aromatic rings optionally substituted with halogen, amino, hydroxy, alkyl or alkoxy, such as phenyl, naphthyl and the like.
  • aryloxy refers to phenoxy, 1-naphthyloxy, 2-naphthyloxy and the like.
  • aralkoxy refers to an alkyl as defined herein substituted with an aromatic carbohydride, such as benzyloxy, phenethoxy, 1-naphthylmethoxy and the like.
  • heteroaryl refers to a monovalent substituent comprising a 5-6 membered monocyclic aromatic system or a 9-10 membered bicyclic aromatic system containing one or more heteroatoms selected from nitrogen, oxygen and sulfur, such as furan, thiophene, pyrrole, imidazole, triazole, pyridine, pyrazine, pyrimidine, oxazole, quinoline, indole, benzimidazole and the like.
  • heteroaryloxy refers to a heteroaryl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, such as pyrrole, imidazole, triazole, pyridine, pyrazine, pyrimidine, oxazole, quinoline, indole, benzimidazole linked to oxygen.
  • heteroaralkoxy refers to a heteroaralkyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, such as (2-furyl)methyl, (3-furyl)methyl, (2-pyridyl)methyl linked to oxygen.
  • acyl refers to a monovalent substituent comprising an alkyl group linked through a carbonyl group, such as acetyl, propionyl, butyryl, isobutyryl, pivaloyl, valeryl and the like.
  • acyloxy refers to an acyl as defined herein linked to an oxygen atom having its free valence bond from the oxygen atom, such as acetyloxy, propionyloxy, butyryloxy, isobutyryloxy, pivaloyloxy, valeryloxy and the like.
  • alkylamino refers to a straight or branched or cyclic monovalent substituent comprising an alkyl group linked through amino having a free valence bond from the nitrogen atom, such as methylamino, ethylamino, propylamino, butylamino, cyclopropylamino, cyclopentylamino, cyclohexylamino and the like.
  • arylamino refers to an aryl as defined herein linked through amino having a free valence bond from the nitrogen atom, such as phenylamino, naphthylamino and the like.
  • aralkylamino refers to an aralkyl as defined herein linked through amino having a free valence bond from the nitrogen atom, such as benzylamino, phenethylamino, 3-phenylpropylamino, 1-naphtylmethylamino and the like.
  • the pharmaceutical composition may be in the forms normally employed, such as tablets, capsules, powders, syrups, solutions, suspensions, aerosols, and the like, may contain flavourants, sweeteners etc. in suitable solids or liquid carriers or diluents, or in suitable sterile media to form injectable solutions or suspensions.
  • the pharmaceutical composition contains up to about 65% of the compounds of Formula I by weight, preferably from about 0.5 to about 40%, more preferably from about 1 to about 20%, and most preferably from about 1 to 10% with the remainder of the composition being pharmaceutically acceptable carriers, diluents or solvents or salt solutions.
  • the term “pharmaceutically acceptable carrier” or “diluent” includes, but is not limited to those disclosed in “Handbook of Pharmaceutical Excipients” published in October, 1986 by American Pharmaceutical Association, the content of which is incorporated herein by reference to the extent permitted.
  • the compounds of the Formula (I) as defined above are clinically administered to mammals, including man and animals, via oral, nasal, transdermal, pulmonary, or parenteral routes. Administration by the oral route is preferred, being more convenient and avoiding the possible pain and irritation of injection.
  • the dosage is in the range from about 0.01 to about 200 mg/kg body weight per day administered singly or as a divided dose, preferably from about 0.01 to about 100 mg/kg and more preferably from about 0.1 to about 50 mg/kg.
  • the optimal dosage for the individual subject being treated will be determined by the person responsible for treatment, generally a smaller dose being administered initially and thereafter increments made to determine the most suitable dosage.
  • any range of numbers recited in the specification or paragraphs hereinafter describing or claiming various aspects of the invention, such as that representing a particular set of properties, units of measure, conditions, physical states or percentages, is intended to literally incorporate expressly herein by reference or otherwise, any number falling within such range, including any subset of numbers or ranges subsumed within any range so recited.
  • the term “about” when used as a modifier for, or in conjunction with, a variable, is intended to convey that the numbers and ranges disclosed herein are flexible and that practice of the present invention by those skilled in the art using temperatures, concentrations, amounts, contents, carbon numbers, and properties that are outside of the range or different from a single value, will achieve the desired result.
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-((2-benzoylphenyl)-amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (60.2 g, 40.1%).
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (75.6 g, 48.1%).
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-((2-nicotinoylphenyl)amino)-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (58.6 g, 39.0%).
  • the crude product is purified by silica gel chromatography using hexane/EtOAc (4:1) as eluent to give 2-[(2-(4-fluorobenzoyl)phenyl)amino]-3-[4-(2-bromoethoxy)-phenyl]-propionic acid methyl ester (429 g, 58%).
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-[(2-(4-tert-butylbenzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (70.7 g, 41.0%).
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-[(2-(4-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (59.1 g, 38%).
  • the solid is filtered and washed with hexane (5 ⁇ 200 ml) to yield the crude 2-[(2-(2-methyl benzoyl)phenyl)-amino]-3-(4-hydroxyphenyl)-propionic acid methyl ester.
  • the crude product is mixed with 250 ml of methanol and is refluxed for 30 min. After cooled to 0° C., the product is filtered, washed with methanol (2 ⁇ 50 ml), and dried under a vacuum to give the title compound (52.9 g, 34%).
  • Activation of RXR/PPARalpha heterodimer by indicated compounds was measured by luciferase reporter assay. Briefly, full length PPARalpha was cloned by PCR using oligonucleotide primers (5′-acgtgcttcctgcttcataga-3′ (SEQ ID NO: 1) and 5′-cctgagattagccacctccc-3′ (SEQ ID NO:2)) from HepG2 cell. The amplified cDNA was cloned into an expression vector and sequenced.
  • the reporter was constructed by insertion of an annealed oligonucleotide containing three copies of the PPAR response element (5′-gatcctctcctttgacctattgaactattacctacatttga-3′ (SEQ ID NO:3)) to the upstream of the luceferase gene in pHD(X3)Luc vector.
  • CV-1 cells were transfected in 96-well plates with the RXR and PPARalpha expression vectors together with the reporter construct. Cells were cultured in media containing the delipidized serum for 24 hours after transfection, then added with tested compounds and positive control WY (WY14643) dissolved in DMSO.
  • DMSO fetal sulfate
  • Activation of RXR/PPARgamma heterodimer was measured by luciferase reporter assay. Briefly, full length PPARgamma was cloned by PCR using oligonucleotide primers (5′-ggggtacctgcttcagcagcgtgttcga-3′ (SEQ ID NO:4) and 5′-gctctagatgttggcagtggctcaggac-3′ (SEQ ID NO: 5)) from adipose tissue. The amplified cDNA was cloned into an expression vector and sequenced.
  • the reporter was constructed by insertion of an annealed oligonucleotide containing 1 copy of the PPAR response element (5′-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3′ (SEQ ID NO:6)) to the upstream of the luceferase gene.
  • CV-1 cells were transfected in 96-well plates with the RXR and PPARgamma expression vectors together with the reporter construct. Cells were cultured in media containing the delipidized serum for 24 hours after transfection, then added with tested compounds and positive control Ros (Rosiglitazone) dissolved in DMSO.
  • DMSO fetal sulfate
  • Activation of RXR/PPARdelta heterodimer was measured by luciferase reporter assay. Briefly, full length PPARdelta was cloned by PCR using oligonucleotide primers (5′-ggggtacctgcttcagcagcgtgttcga-3′ (SEQ ID NO:4) and 5 ′-gctctagatgttggcagtggctcaggac-3′ (SEQ ID NO:5)) from adipose tissue. The amplified cDNA was cloned into an expression vector and sequenced.
  • the reporter was constructed by insertion of an annealed oligonucleotide containing 1 copy of the PPAR response element (5′-cgcgttcctttccgaacgtgacctttgtcctggtccccttttgct-3′ (SEQ ID NO:6)) to the upstream of the luceferase gene.
  • CV-1 cells were transfected in 96-well plates with the RXR and PPARdelta expression vectors together with the reporter construct. Cells were cultured in media containing the delipidized serum for 24 hours after transfection, then added with tested compounds and positive control 2-Bro (2-Bromohexadecanoic acid) dissolved in DMSO.
  • DMSO fetal sulfate

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PT03772525T PT1569904E (pt) 2002-11-26 2003-11-21 Derivados substituídos do ácido arilalcanóico como agonistas ppar pan com potente actividade antihiperglicémica e anti-hiperlipidémica
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